Immunoprophylaxis - Acquired Immunodeficiency Syndrome

Immunoprophylaxis

A great effort is underway to develop a vaccine against HIV. Different groups are exploring a variety of approaches. Attenuated vaccines, based on creating genetically engineered strains lacking some crucial genes so that the resulting virus causes a harmless in-fection, have been tried successfully with simian immunodeficiency virus (SIV) and an attenuated vaccine may be field-tried soon. Inactivated vaccines have not been shown to induce protective antiviral immunity in animal trials using SIV. However, there has been considerable interest in using killed vaccines to prevent the emergence of clinical disease. It has been proposed that vaccination with low doses of killed HIV boosts TH1 responses and favors the development of cell-mediated cytotoxicity. However, the evaluation of the efficacy of this approach is complicated by the fact that the endpoint for evaluation is the disease-free interval, rather long and variable. Recombinant viral particles made by in-serting HIV glycoprotein genes in vaccinia virus or canary poxvirus genomes, for exam-ple, have been shown to induce neutralizing antibodies in animals. These vaccines seem to be the most prone to stimulate the differentiation of HIV-specific MHC-I–restricted cytotoxic lymphocytes. Component vaccines have been prepared using isolated gp120, polymerized gp120, or gp120 peptides representing more conserved regions (such as the CD4-binding domain). Recently, Tat protein vaccines have been proposed, with the ra-tionale that antibodies to this protein will prevent the intercellular transactivation of HIV replication mediated by soluble Tat protein. Finally, DNA vaccines also appear to induce HIV-specific MHC-I–restricted cytotoxic lymphocytes and have been found to induce protection in primates.

In spite of all these attempts, progress in the development of an effective HIV vac-cine has been slow. Difficulties in evaluation of candidate vaccines, due to the relative in-adequacy of animal models and the lack of adequate indices of protection in humans, have slowed down progress. Most commonly, the assessment of the efficacy of a vaccine is based on the assay of protective antibodies. However, antibodies are not truly protective in the case of HIV; in most cases the antibodies induced by gp120 do not neutralize primary HIV isolates.

       All evidence points to the fact that an efficient vaccine should stimulate the differen-tiation of HIV-specific cytotoxic T lymphocytes, which may be the only way to eliminate viral-infected cells, which apparently can be involved in the transmission of HIV infection. Certain conserved epitopes of gp120, gp41, and of the Gag protein appear more effective in inducing T-cell–mediated immunity. A trial with a recombinant vaccinia virus express-ing a gag epitope demonstrated that it effectively induces CD8+ cells with cytotoxic activ-ity specifically directed to it. Other poxviruses, such as canary pox, have also been shown to be effective vectors from the point of view of inducing cytotoxic responses. A problem unique to this approach is that the assessment of cell-mediated cytotoxicity is much more laborious and expensive than the assessment of humoral immunity.

Case 30.1 Revisited

The onset of Pneumocystis carinii in a previously healthy young adult with low T-cell count and evidence suggestive of mucocutaneous candidiasis should raise the possibility of the diagnosis of AIDS.

Two important tests should be immediately ordered in this patient: (1) because of the lymphopenia during an acute infection, a lymphocyte subpopulation profile should be or-dered; and (2) because of the suspected diagnosis of AIDS, HIV serologies should also be ordered. This patient had a profound CD4+ lymphocyte deficiency (4/ µL) and was HIV-positive both by EIA and by Western blot.

A patient with profound depression of the CD4+ lymphocyte count is at risk for all types of infections by pathogenic and opportunistic agents, including bacteria, viruses, fungi, and parasites. This patient has mucosal candidiasis at the time of diagnosis and de-veloped a systemic infection with Mycobacterium avium-intracellulare soon thereafter.

       At the time of diagnosis the most pressing issue was the Pneumocystis carinii pneu-monia, which was treated with IV sulfamethoxazole-trimethoprim (SMZ-TMP). At the same time, oral fluconazole was started to control the mucosal candidiasis. Antiretroviral ther-apy was delayed until the patient could be placed on a maintenance dose of SMZ-TMP, be-cause of the combined risk of bone marrow depression that is associated to the simultane-ous administration of antiretrovirals (particularly ZDV and SMZ-TMP in high doses, as required in a case of Pneumocystis carinii pneumonia). The diagnosis of disseminated infection with Mycobacterium avium-intracellulare was followed by administration of clarithromycin and ethambutol. After the resolution of the acute infections that affected this patient, he was placed on HAART plus chemoprophylaxis with a combination of SMZ-TMP, clarithromycin, and fluconazole, and was instructed to receive periodical S. pneu-moniae and influenza immunizations. Prevention of infections has resulted in prolonged survival for patients with AIDS.